Re-Purposing Sapropterin (Kuvan) for ACTA2-Related Multisystemic Smooth Muscle Dysfunction Syndrome: A Translational...

Multisystemic smooth muscle dysfunction syndrome (MSMDS) is an ultra-rare, ACTA2-related disorder characterized by severe cerebrovascular disease, aortic aneurysms, and smooth muscle dysfunction. Using molecular dynamics simulations and in silico drug screening, we identified that sapropterin dihydrochloride (Kuvan) is a candidate capable of restoring p.R179H mutation disrupted actin polymerization. Patient-derived fibroblasts demonstrated improved actin organization with Kuvan treatment. Off-label treatment in a single pediatric patient with ACTA2-MSMDS resulted in observed cerebrovascular stabilization and clinical improvement on longitudinal follow-up. These findings provide first-in-human n-of-1 translational evidence supporting sapropterin as a potential disease-modifying therapy for ACTA2-related vasculopathies, while gene-directed therapies are awaited. Further studies are needed to establish a robust therapeutic effect and to elucidate the mechanisms underlying the observed cerebrovascular benefit.